A highly potent and selective inhibitor Roxyl-WL targeting IDO1 promotes immune response against melanoma

<p>Indoleamine 2,3-dioxygenase 1 (IDO1) activity links to immune escape of cancers. Inhibition of IDO1 provides a new approach for cancer treatment. Most clinical IDO1 drugs show marginal efficacy as single agents. On basis of molecular docking and pharmacophore modelling, a novel inhibitor Roxyl-WL was discovered with a half maximal inhibitory concentration (IC50) value of 1 nM against IDO1 and 10–100-fold increased potent activity compared with IDO1 drugs in clinical trials. Roxyl-WL displayed excellent kinase spectrum selectivity with no activity out of the 337 protein kinases. <i>In vitro</i>, Roxyl-WL effectively augmented the proliferation of T cells and reduced the number of regulatory T cell (Tregs).When administered to melanoma (B16F10) tumor-bearing mice orally, Roxyl-WL significantly suppressed tumor growth and induced immune response.</p

Discovery of Small Molecule Agonist of Gonadotropin-Releasing Hormone Receptor (GnRH1R)

The gonadotrophin-releasing hormone (GnRH) is a central regulator of the human reproductive system and exerts physiological effects by binding to GnRH1R. The GnRH–GnRH1R system is a promising therapeutic target for the maintenance of reproductive function. There are several GnRH1R agonists on the market, but like GnRH, they are all peptide compounds and are limited by their way of administration (subcutaneous or intramuscular injection). To date, no published GnRH1R small molecule agonists have been reported. In this paper, the HTRF-based screening method has been used to screen our in-house chemical library, and we found and confirmed CD304 as a hit compound. Subsequently, structure optimization led to the discovery of compound 6d, exhibited with a certain GnRH1R activation activity (EC50: 1.59 ± 0.38 μM). Further molecular dynamics simulation experiments showed that 6d can well bind to the orthosteric site of GnRH1R through forming a hydrogen-bonding interaction with Y2836.51. Binding of 6d further induces conformational changes in TM6 and TM7, promoting the formation of a continuous water channel in GnRH1R, thereby promoting GnRH1R activation. This well-characterized hit compound will facilitate the further development of novel small molecule agonists of GnRH1R

Discovery of Small Molecule Agonist of Gonadotropin-Releasing Hormone Receptor (GnRH1R)

The gonadotrophin-releasing hormone (GnRH) is a central regulator of the human reproductive system and exerts physiological effects by binding to GnRH1R. The GnRH–GnRH1R system is a promising therapeutic target for the maintenance of reproductive function. There are several GnRH1R agonists on the market, but like GnRH, they are all peptide compounds and are limited by their way of administration (subcutaneous or intramuscular injection). To date, no published GnRH1R small molecule agonists have been reported. In this paper, the HTRF-based screening method has been used to screen our in-house chemical library, and we found and confirmed CD304 as a hit compound. Subsequently, structure optimization led to the discovery of compound 6d, exhibited with a certain GnRH1R activation activity (EC50: 1.59 ± 0.38 μM). Further molecular dynamics simulation experiments showed that 6d can well bind to the orthosteric site of GnRH1R through forming a hydrogen-bonding interaction with Y2836.51. Binding of 6d further induces conformational changes in TM6 and TM7, promoting the formation of a continuous water channel in GnRH1R, thereby promoting GnRH1R activation. This well-characterized hit compound will facilitate the further development of novel small molecule agonists of GnRH1R

Discovery of New SIRT2 Inhibitors by Utilizing a Consensus Docking/Scoring Strategy and Structure–Activity Relationship Analysis

SIRT2, which is a NAD+ (nicotinamide adenine dinucleotide) dependent deacetylase, has been demonstrated to play an important role in the occurrence and development of a variety of diseases such as cancer, ischemia-reperfusion, and neurodegenerative diseases. Small molecule inhibitors of SIRT2 are thought to be potential interfering agents for relevant diseases. Discovery of SIRT2 inhibitors has attracted much attention recently. In this investigation, we adopted a consensus docking/scoring strategy to screen for novel SIRT2 inhibitors. Structural optimization and structure–activity relationship (SAR) analysis were then carried out on highly potent compounds with new scaffolds, which led to the discovery of 2-((5-benzyl-5<i>H</i>-[1,2,4]­triazino­[5,6-<i>b</i>]­indol-3-yl)­thio)-<i>N</i>-(naphthalen-1-yl)­acetamide (<b>SR86</b>). This compound showed good activity against SIRT2 with an IC₅₀ value of 1.3 μM. <b>SR86</b> did not exhibit activity against SIRT1 and SIRT3, implying a good selectivity for SIRT2. In in vitro cellular assays, <b>SR86</b> displayed very good antiviability activity against breast cancer cell line MCF-7. In Western blot assays, <b>SR86</b> showed considerable activity in blocking the deacetylation of α-tubulin, which is a typical substrate of SIRT2. Collectively, because of the new scaffold structure and good selectivity of <b>SR86</b>, it could serve as a promising lead compound, hence deserving further studies

Discovery of <i>N</i>1‑(4-((7-Cyclopentyl-6-(dimethylcarbamoyl)‑7<i>H</i>‑pyrrolo[2,3‑<i>d</i>]pyrimidin-2-yl)amino)phenyl)‑<i>N</i>8‑hydroxyoctanediamide as a Novel Inhibitor Targeting Cyclin-dependent Kinase 4/9 (CDK4/9) and Histone Deacetlyase1 (HDAC1) against Malignant Cancer

A series of novel, highly potent, selective inhibitors targeting both CDK4/9 and HDAC1 have been designed and synthesized. <i>N</i>1-(4-((7-Cyclopentyl-6-(dimethylcarbamoyl)-7<i>H</i>-pyrrolo­[2,3-<i>d</i>] pyrimidin-2-yl)­amino)­phenyl)-<i>N</i>8-hydroxyoctanediamide (<b>6e</b>) was discovered. The lead compound <b>6e</b> with excellent CDK4/9 and HDAC1 inhibitory activity of IC₅₀ = 8.8, 12, and 2.2 nM, respectively, can effectively induce apoptosis of cancer cell lines. The kinase profiling of compound <b>6e</b> showed excellent selectivity and specificity. Compound <b>6e</b> induces G2/M arrest in high concentration and G0/G1 arrest in low concentration to prevent the proliferation and differentiation of cancer cells. Mice bared-breast cancer treated with <b>6e</b> showed significant antitumor efficacy. The insight into mechanisms of <b>6e</b> indicated that it could induce cancer cell death via cell apoptosis based on CDK4/9 and HDAC1 repression and phosphorylation of p53. Our data demonstrated the novel compound <b>6e</b> could be a promising drug candidate for cancer therapy

Highly Selective, Potent, and Oral mTOR Inhibitor for Treatment of Cancer as Autophagy Inducer

On the basis of novel pyrazino­[2,3-<i>c</i>]­quinolin-2­(1<i>H</i>)-one scaffold, we designed and identified a highly selective, potent and oral mTOR inhibitor, <b>9m</b>. Compound <b>9m</b> showed low nanomolar activity against mTOR (IC₅₀ = 7 nM) and greater selectivity over the related PIKK family kinases, which demonstrated only modest activity against 3 out of the 409 protein kinases. In vitro assays, compound <b>9m</b> exhibited high potency against human breast and cervical cancer cells and induced tumor cell cycle arrest and autophagy. <b>9m</b> inhibited cellular phosphorylation of mTORC1 (pS6 and p4E-BP1) and mTORC2 (pAKT (S473)) substrates. In T-47D xenograft mouse model, oral administration of compound <b>9m</b> led to significant tumor regression without obvious toxicity. In addition, this compound showed good pharmacokinetics. Collectively, due to its high potency and selectivity, compound <b>9m</b> could be used as a mTOR drug candidate